Anti-CD22 CAR-T Cell Therapy as a Salvage Treatment in B Cell Malignancies Refractory or Relapsed After Anti-CD19 CAR-T therapy

Abstract

Background: To observe efficacy of the anti-CD22 chimeric antigen receptor modified (anti-CD22-CAR) T cell salvage therapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and B cell acute lymphoid leukemia (B-ALL) patients whose disease did not reach CR or progressed again after anti-CD19-CAR T cell therapy.

Methods: In our study, seven R/R DLBCL patients reached stable disease (SD) or progression of disease (PD) after their anti-CD19-CAR T cell therapy. Only three in all the six R/R B-ALL patients obtained complete response (CR)/CR with incomplete count recovery (Cri) in their anti-CD19-CAR T cell therapy, but they relapsed again in the following three, six and one months. Then, all these thirteen R/R DLBCL and B-ALL patients received anti-CD22 CAR-T cell salvage therapy because their disease did not reach CR or progressed again.

Results: Four R/R DLBCL patients obtained CR, while two R/R DLBCL patients achieved PR and one patient achieved SD. But only two R/R B-ALL patients obtained Cri in their anti-CD22 CAR-T cell salvage therapy. The overall survival (OS) of R/R DLBCL patients after the anti-CD22 CAR-T cell therapy was 6.142±3.395 months until August 31, 2020. There was no different of the median expansion peaks of the two kinds of CAR T cells (P=0.920). The time of anti-CD22-CAR T cell proportion peak days was later than that of the time of anti-CD19-CAR T cell peak days post infusion (P=0.022). Their cytokine release syndrome (CRS) was graded 2-4 in their anti-CD19-CAR T cell therapy, while the notable CRS was graded 1-2 in their anti-CD22-CAR T cell therapy. But there was no difference in the CRS and the immune effect or cell associated neurotoxic syndrome (ICANS) grades in the two kinds of therapies. And there was no difference in the hematological toxicity grades in the two kinds of therapies.

Conclusion: The anti-CD22-CAR T cell salvage therapy is highly effective in R/R DLBCL patients than in R/R B-ALL patients who failed in anti-CD19-CAR T cell therapy before. We need to expand the number of R/R DLBCL or B-ALL patients and continue to observe.

Trial registration: ChiCTR-ONN-16009862 and ChiCTR1800019298.

Keywords: CAR; acute lymphoblastic leukemia; anti-CD19; anti-CD22; chimeric antigen receptor; diffuse large B-cell lymphoma.

Figure 1

CD19 and CD22 antigen expression on malignant B cells in the six R/R B-ALL patients. (A, C, E, G, I, K). High expression ofCD19 antigen on malignant B cells in the six R/R B-ALL patients before anti-CD19-CAR T cell therapy. (B, D, F, H, J, L). Normal or low expression of CD19 antigen, with high expression of CD22 antigen on malignant B cells in the six R/R B-ALL patients before anti-CD22-CAR T cell therapy.

Figure 2

Clinical responses to the two kinds of CAR-T cell therapy. (A). Clinical responses and survival time of all the thirteen R/R DLBCL and B-ALL patients. (B). Clinical responses to the two kinds of CAR-T cell therapy in the seven R/R DLBCL patients. (C). Clinical responses to the two kinds of CAR-T cell therapy in the six R/R B-ALL patients. D. PFS and OS in the R/R DLBCL and B-ALL patients after their anti-CD22-CAR T cell therapy.

Figure 3

The proportions of two kinds of CAR-T cells, the levels of two kinds of CAR DNA in peripheral blood. (A and B). The proportions of two kinds of CAR-T cells on 0, 4, 7, 14, 21, 28 days post the CAR-T cell infusion. (C and D). The levels of two kinds of CAR DNA on 0, 4, 7, 14, 21, 28 days post the CAR-T cell infusion.

Figure 4

Different of the expansion of the two kinds of CAR-T cells. (A) There was no different of the median expansion peaks of the two kinds of CAR-T cells (P=0.920). (B). The time of anti-CD22-CAR T cell proportion peak were later than that of the time of anti-CD19-CAR T cell peak (P=0.022). (C). There was no different of the median peak of the two kinds of CAR DNA (P=0.880). (D). The time ofCD22 CAR DNA peak were later than that of the time of CD19 CAR DNA peak (P=0.001).

Figure 5

Grades of CRS, ICANS and hematological toxicity in the two kinds of CAR-T cell therapy. (A). There was no different of the CRS grades in the two kinds of therapy. (B). There was no different of the ICANS grades in the two kinds of therapy. (C-E). There was no different of the hematological toxicity grades in the two kinds of therapies.

Figure 6

The serum levels of IL-6, IL-2R, IL-8 and TNF-α in anti-CD19-CAR T cell and anti-CD22-CAR T cell therapy. (A). The serum levels of IL-6 in anti-CD19-CAR T cell therapy. (B). The serum levels of IL-8 in anti-CD19-CAR T cell therapy. (C). The serum levels of IL-2R in anti-CD19-CAR T cell therapy. (D). The serum levels of TNF-α in anti-CD19-CAR T cell therapy. (E). The serum levels of IL-6 in anti-CD22-CAR T cell therapy. (F). The serum levels of IL-8 in anti-CD22-CAR T cell therapy. (G). The serum levels of IL-2R in anti-CD22-CAR T cell therapy. (H). The serum levels of TNF-α in anti-CD22-CAR T cell therapy.

Figure 7

Different of the peaks and peak times of the serum cytokines. (A-D). The peaks of IL-6, IL-2R and TNF-α were higher in anti-CD19-CAR T cell therapy than that of in anti-CD22-CAR T cell therapy. (E-H). The time of the mean peaks of IL-6, IL-2R and TNF-α in anti-CD22-CAR T cell therapy were later than that of the time in anti-CD19-CAR T cell therapy.